Cytoplasmic Translocation of the Transcription Factor pCREB and Altered Proteostasis in Human Islet Cells During Type 1 Diabetes Development

Abstract

Type 1 diabetes is an autoimmune disease that leads to beta cell death. To test whether beta cell defects precede diagnosis, the expression of pCREB was surveyed in human islet cells. pCREB is a transcription factor produced by islet cells that regulates the expression of islet cell–specific genes. This analysis indicated that while islet cells of control donors displayed CREB/pCREB in the nucleus of alpha and beta cells, the transcription factor was also found in the cytoplasm of islet cells of normoglycemic GADA donors, donors with two antibodies and of those recently diagnosed. The translocation of CREB/pCREB, which decreases its activity, was correlated with reduced or absent expression of insulin and a protease. These changes suggest an alteration in protein homeostasis. The cytoplasmic localization of CREB/pCREB was transient, since the transcription factor moved to the nuclei of insulin cells of donors with longer standing disease. The fact that altered proteostasis leads to autoinflammation suggests that interventions at an initial stage of the disease, when protein homeostasis could be restored, may prevent the progress of the disease.